Proteome-Wide Mendelian Randomization Identifies Causal Links Between Blood Proteins and Acute Pancreatitis

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Acute pancreatitis (AP) is a complex disease and the leading cause of gastrointestinal disease-related hospital admissions. Few therapeutic options exist for AP prevention. Blood proteins with causal evidence may represent promising drug targets, but few have been causally linked with AP. Our objective was to identify blood proteins linked with AP by combining genome-wide association meta-analysis and proteome-wide Mendelian randomization (MR) studies. We performed a genome-wide association meta-analysis totalling 10,630 patients with AP and 844,679 controls and a series of inverse-variance weighted MR analyses using cis-acting variants on 4719 blood proteins from the deCODE study (N= 35,559) and 4979 blood proteins from the Fenland study (N= 10,708). The meta-analysis identified genome-wide significant variants (P <5× 10-8) at 5 loci (ABCG5/8, TWIST2, SPINK1, PRSS2 and MORC4). The proteome-wide MR analyses identified 68 unique blood proteins that may causally be associated with AP, including 29 proteins validated in both data sets. Functional annotation of these proteins confirmed expression of many proteins in metabolic tissues responsible for digestion and energy metabolism, such as the esophagus, adipose tissue, and liver as well as acinar cells of the pancreas. Genetic colocalization and investigations into the druggable genome also identified potential drug targets for AP. This large genome-wide association study meta-analysis for AP identified new variants linked with AP as well as several blood proteins that may be causally associated with AP. This study provides new information on the genetic architecture of this disease and identified pathways related to AP, which may be further explored as possible therapeutic targets forAP.